Lung cancer is the leading cause of cancer-related death for men and women in the U.S. The susceptibility of the chronic smoker for developing lung cancer is likely linked to germ-line polymorphisms in critical genes involved in the bioactivation, detoxification, and repair of DNA damage stemming from tobacco carcinogens and the subsequent acquisition of somatic genetic and epigenetic changes in critical regulatory genes. Epigenetically mediated gene silencing through promoter hypermethylation is a common event that is critical for initiation and progression of cancer. Population-based studies of cancer-free male and female smokers have not been conducted to evaluate the interrelationships between clinical risk factors, germ-line, and somatic changes for their contribution to lung cancer development. In support of this approach, we have demonstrated that aberrant methylation of the pl6 and/or O6-methylguanine-DNA methyltransferase (MGMT) promoters can be detected in DNA from sputum in 100% of squamous cell lung carcinomas (SCCs) up to 3 years before clinical diagnosis. The extension of these findings to a nested, case-control study revealed that the presence of any one of four methylation markers examined was associated with a 6.3 fold increase in risk for incident lung cancer. In addition, we conducted a pilot study to determine whether germ-line mutations in lung cancer susceptibility genes are associated with the presence of methylated alleles of p 16 and MGMT in sputum from cancer-free, high-risk subjects. Risk alleles for the genes encoding the NAD(P)H quinone oxidoreductase and glutathione-S-transferase P1 genes were significantly associated with methylation of the pl6 or MGMT genes. These findings will be extended to integrate metabolic susceptibility factors with genetic biomarkers and clinical risk factors to better understand the etiology of lung cancer.
Four specific aims will be accomplished through a cross-sectional and longitudinal study using 1500 subjects, 750 from each of the two existing cohorts of current and former smokers, a 2,250-person cohort of veterans, and a 1,500-person female cohort. The first will determine whether the risk alleles for genes involved in tobacco carcinogen activation and detoxification, oxidative stress, DNA repair, and de novo methylation of CpG sites are associated with gene-specific promoter hypermethylation in sputum.
The second aim will determine whether diet and/or the established clinical risk factors COPD and smoking history are associated with DNA methylation detected in exfoliated cells within sputum.
The third aim will determine whether the effect of clinical risk factors that include smoking on methylation patterns vary as a function of genotype. Finally we will describe the gene-specific promoter hypermethylation patterns at study entry and at 18-month follow-up.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA097356-01A2
Application #
6731676
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Kagan, Jacob
Project Start
2004-09-23
Project End
2009-08-31
Budget Start
2004-09-23
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$920,685
Indirect Cost
Name
Lovelace Biomedical & Environmental Research
Department
Type
DUNS #
045911138
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
Leng, Shuguang; Diergaarde, Brenda; Picchi, Maria A et al. (2018) Gene Promoter Hypermethylation Detected in Sputum Predicts FEV1 Decline and All-Cause Mortality in Smokers. Am J Respir Crit Care Med 198:187-196
Leng, Shuguang; Picchi, Maria A; Kang, Huining et al. (2018) Dietary Nutrient Intake, Ethnicity, and Epigenetic Silencing of Lung Cancer Genes Detected in Sputum in New Mexican Smokers. Cancer Prev Res (Phila) 11:93-102
Belinsky, Steven A; Leng, Shuguang; Wu, Guodong et al. (2017) Gene Methylation Biomarkers in Sputum and Plasma as Predictors for Lung Cancer Recurrence. Cancer Prev Res (Phila) 10:635-640
Leng, Shuguang; Wu, Guodong; Klinge, Donna M et al. (2017) Gene methylation biomarkers in sputum as a classifier for lung cancer risk. Oncotarget 8:63978-63985
Leng, Shuguang; Picchi, Maria A; Tesfaigzi, Yohannes et al. (2017) Dietary nutrients associated with preservation of lung function in Hispanic and non-Hispanic white smokers from New Mexico. Int J Chron Obstruct Pulmon Dis 12:3171-3181
Bruse, Shannon; Moreau, Michael; Bromberg, Yana et al. (2016) Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility. Hum Genomics 10:1
Leng, Shuguang; Weissfeld, Joel L; Picchi, Maria A et al. (2016) A prospective and retrospective analysis of smoking behavior changes in ever smokers with high risk for lung cancer from New Mexico and Pennsylvania. Int J Mol Epidemiol Genet 7:95-104
Tellez, Carmen S; Juri, Daniel E; Do, Kieu et al. (2016) miR-196b Is Epigenetically Silenced during the Premalignant Stage of Lung Carcinogenesis. Cancer Res 76:4741-51
Leng, Shuguang; Wu, Guodong; Collins, Leonard B et al. (2015) Implication of a Chromosome 15q15.2 Locus in Regulating UBR1 and Predisposing Smokers to MGMT Methylation in Lung. Cancer Res 75:3108-17
Meek, Paula M; Sood, Akshay; Petersen, Hans et al. (2015) Epigenetic change (GATA-4 gene methylation) is associated with health status in chronic obstructive pulmonary disease. Biol Res Nurs 17:191-8

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